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Clinical response to ibrutinib is accompanied by normalization of the T-cell environment in CLL-related autoimmune cytopenia

Leukemia volume 30, pages 2232–2234 (2016)Cite this article

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Autoimmune cytopenia (AIC) represents a clinical challenge in about 5–10% of patients with chronic lymphocytic leukemia (CLL) at some point during the course of their disease.1, 2, 3 Most commonly, patients present with autoimmune hemolytic anemia (AIHA) or immune thrombocytopenia (ITP), while the risk of developing autoimmune neutropenia (AIN) or pure red cell aplasia (PRCA) is considerably lower and these conditions are generally harder to treat.1, 2, 3, 4 The pathophysiological events driving AIC in CLL are complex and still insufficiently understood. A growing body of evidence, however, suggests that—except from rare cases of AIHA mediated by cold agglutinins with VH4-34 usage (direct anti-I/i activity)—the majority of AIC seems to be mediated by polyclonal B- and T-cell responses rather than by the malignant B-cell clone.5, 6 Profound CLL-specific T-cell deficiencies as well as (red blood cell) autoantigen presentation by CLL cells may create an immunological environment permitting the escape of self-reactive T cells and pathological autoantibody production by non-malignant B cells.7, 8, 9

The licensing of B-cell receptor pathway inhibitors such as the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib has considerably changed our management of CLL patients and invites us to revisit our current approach to the patient with CLL-associated AIC based on first clinical experiences with this drug in this specific setting.10, 11 BTK is not only expressed in B cells, but also in other effector cells like macrophages, monocytes and mast cells that may be relevant in the autoimmune setting. Moreover, ibrutinib also irreversibly inhibits the interleukin-2-inducible T-cell kinase (ITK) expressed by T cells, natural killer (NK) T cells and NK cells. ITK inhibition abrogates Th2 immune responses, thereby, potentiating Th1 responses.12 In line with this, ibrutinib shows exceptional activity in a preclinical rheumatoid arthritis mouse model and BTK/ITK inhibition is currently under investigation in clinical trials for autoimmune disorders.13, 14 This broad immunomodulatory profile of ibrutinib suggests that this compound would also have a positive impact on AIC associated with CLL, and first analyses of such patients treated on clinical trials underscore this assumption. These investigations mainly included patients with the relatively common AIHA and ITP showing that the majority could discontinue AIC treatment under therapy with ibrutinib.10, 11 Likewise, treatment-emergent AIC was reported to be low, but a flare after initiation of ibrutinib might require intermittent intensification of the AIC-directed therapy. As the initial flare was mostly temporary, long-term single-agent treatment with ibrutinib was feasible in the majority of cases (7 of 9 patients).11

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References

  1. Mauro FR, Foa R, Cerretti R, Giannarelli D, Coluzzi S, Mandelli F et al. Autoimmune hemolytic anemia in chronic lymphocytic leukemia: clinical, therapeutic, and prognostic features. Blood 2000; 95: 2786–2792.

    CAS  PubMed  Google Scholar 

  2. Zent CS, Ding W, Schwager SM, Reinalda MS, Hoyer JD, Jelinek DF et al. The prognostic significance of cytopenia in chronic lymphocytic leukaemia/small lymphocytic lymphoma. Br J Haematol 2008; 141: 615–621.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Moreno C, Hodgson K, Ferrer G, Elena M, Filella X, Pereira A et al. Autoimmune cytopenia in chronic lymphocytic leukemia: prevalence, clinical associations, and prognostic significance. Blood 2010; 116: 4771–4776.

    Article  CAS  PubMed  Google Scholar 

  4. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 2008; 111: 5446–5456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Visco C, Barcellini W, Maura F, Neri A, Cortelezzi A, Rodeghiero F . Autoimmune cytopenias in chronic lymphocytic leukemia. Am J Hematol 2014; 89: 1055–1062.

    Article  CAS  PubMed  Google Scholar 

  6. Ruzickova S, Pruss A, Odendahl M, Wolbart K, Burmester G-R, Scholze J et al. Chronic lymphocytic leukemia preceded by cold agglutinin disease: intraclonal immunoglobulin light-chain diversity in V(H)4-34 expressing single leukemic B cells. Blood 2002; 100: 3419–3422.

    Article  CAS  PubMed  Google Scholar 

  7. Beyer M, Kochanek M, Darabi K, Popov A, Jensen M, Endl E et al. Reduced frequencies and suppressive function of CD4+CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood 2005; 106: 2018–2025.

    Article  CAS  PubMed  Google Scholar 

  8. Hall AM, Vickers MA, McLeod E, Barker RN . Rh autoantigen presentation to helper T cells in chronic lymphocytic leukemia by malignant B cells. Blood 2005; 105: 2007–2015.

    Article  CAS  PubMed  Google Scholar 

  9. Lad DP, Varma S, Varma N, Sachdeva MUS, Bose P, Malhotra P . Regulatory T-cells in B-cell chronic lymphocytic leukemia: their role in disease progression and autoimmune cytopenias. Leuk Lymphoma 2013; 54: 1012–1019.

    Article  CAS  PubMed  Google Scholar 

  10. Rogers KA, Ruppert AS, Bingman A, Andritsos LA, Awan FT, Blum KA et al. Incidence and description of autoimmune cytopenias during treatment with ibrutinib for chronic lymphocytic leukemia. Leukemia 2016; 30: 346–350.

    Article  CAS  PubMed  Google Scholar 

  11. Vitale C, Ahn IE, Sivina M, Ferrajoli A, Wierda WG, Estrov Z et al. Autoimmune cytopenias in patients with chronic lymphocytic leukemia treated with ibrutinib. Haematologica 2016; 101: e254–e258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Dubovsky JA, Beckwith KA, Natarajan G, Woyach JA, Jaglowski S, Zhong Y et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood 2013; 122: 2539–2549.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Honigberg LA, Smith AM, Sirisawad M, Verner E, Loury D, Chang B et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci USA 2010; 107: 13075–13080.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Akinleye A, Chen Y, Mukhi N, Song Y, Liu D . Ibrutinib and novel BTK inhibitors in clinical development. J Hematol Oncol 2013; 6: 59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Oncology and Hematology, BMT with Section Pneumology, Hubertus Wald Tumorzentrum/UCCH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    S Schliffke, N Akyüz, C T Ford, T Mährle, C Bokemeyer & M Binder

  2. LYTIQ GmbH, Paderborn, Germany

    T Thenhausen & A Krohn-Grimberghe

  3. Department of Medicine II, Hematology and Oncology, University Hospital of Würzburg, Würzburg, Germany

    S Knop

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  1. S Schliffke
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Correspondence to M Binder.

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Author contributions

MB designed the study, supervised the experiments and wrote the manuscript. SS analyzed clinical data, performed the next-generation sequencing preparation and data analysis, and contributed to writing of the manuscript. NA performed next-generation sequencing and data analysis. CF performed next-generation sequencing and data analysis. TM performed the next-generation sequencing preparation. TT and AG provided the data analysis platform. SK provided patient material, interpreted the data and critically revised the manuscript. CB interpreted data and critically revised the manuscript. All authors reviewed the manuscript and approved the final version.

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Schliffke, S., Akyüz, N., Ford, C. et al. Clinical response to ibrutinib is accompanied by normalization of the T-cell environment in CLL-related autoimmune cytopenia. Leukemia 30, 2232–2234 (2016). https://doi.org/10.1038/leu.2016.157

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